US7179918B2ExpiredUtilityPatentIndex 47
HIV protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for their synthesis
Est. expiryJun 11, 2021(expired)· nominal 20-yr term from priority
Inventors:CANAN KOCH STACIE SALEXANDER THERESE NBURKE BENJAMIN JJEWELL TANYA MKUCERA DAVID JLINTON MARIA ANGELICAMITCHELL JR LENNERT JREICH SIEGFRIED HSKALITZKY DONALD JTATLOCK JOHN HVARNEY MICHAEL DVIRGIL SCOTT CWEBBER STEPHEN EWORLAND STEPHEN TBARVIAN MARKBOLTON GARYBOYER JR FREDERICK EARLMACHAK JEFFREY JHOLLER TODMURPHY SEAN TMELNICK MICHAELJOSYULA VARA PRASAD
A61P 31/18A61P 31/12A61P 43/00A61P 37/02A61P 31/00C07D 277/60C07D 295/13C07D 277/06C07D 307/52C07D 213/38C07D 409/12C07D 207/09A61K 31/427C07D 417/12C07D 231/12C07D 417/14C07D 217/26C07D 471/08C07D 405/12C07D 413/12C07D 207/16A61K 31/426
47
PatentIndex Score
0
Cited by
87
References
24
Claims
Abstract
Compounds of the formula: where the formula variables are as defined herein, are disclosed that advantageously inhibit or block the biological activity of the HIV protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with the HIV virus. Intermediates and synthetic methods for preparing such compounds are also described.
Claims
exact text as granted — not AI-modified1. A compound of the Formula I-A:
wherein:
R 1 is a 3-, 4-, or 7-membered mono-cyclic carbocyclic group;
R 2 is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;
R 2′ is H or a C 1 –C 6 alkyl group;
or R 2 and R 2′ taken together with the nitrogen atom to which they are attached form an unsubstituted or substituted heterocyclic ring;
X is
wherein R x is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;
R 8 and R 8′ are each independently H, halo or a C 1 –C 4 aliphatic group;
Z is CH 2 , CHF, CF 2 , CH(OH), CH(O—R Z ), CH(N—R Z R Z′ ),
CH(S—R Z ), C(═O), or CH(R Z ), where R Z is a C 1 –C 6 aliphatic group or a carbocyclic or heterocyclic group and R Z′ is H or a C 1 –C 6 aliphatic group;
R 3 is H or a C 1 –C 6 aliphatic group;
R 4 and R 5 are independently selected from H, halo, a C 1 –C 6 aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′ is an aliphatic, carbocyclic or heterocyclic group;
R 6 and R 7 are independently selected from H, halo or a C 1 –C 6 aliphatic group;
wherein any of said aliphatic groups are unsubstituted or substituted by one or more suitable substituents and saturated, partially unsaturated or fully unsaturated; and
wherein any of said carbocyclic or heterocyclic groups are mono-, bi- or tri-cyclic saturated, partially unsaturated or fully unsaturated or unsubstituted or substituted by one or more suitable substituents;
provided that R 2 is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when Z is CHF or CH 2 ; R 2′ , R 3 , R 8 and R 8′ are H or a C 1 –C 4 alkyl group; R 4 , R 5 , R 6 and R 7 are H or a C 1 –C 6 alkyl group; X is
and R 1 is a substituted or unsubstituted 5- or 6-membered mono-cyclic carbocyclic group;
or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.
2. A compound of the Formula I-D:
wherein:
R 1 is a carbocyclic group;
R 2 is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;
W is N;
R 2′ is H or a C 1 –C 6 alkyl group or R 2 and R 2′ taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring;
X is
R x is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;
R 8 and R 8′ are each independently H, halo or a C 1 –C 4 aliphatic group;
Z is CH 2 , CF 2 , CHF, CH(OH), CH(O—R Z ), CH(N—R Z R Z′ ),
CH(S—R Z ), C(═O), or CH(R Z ), where R Z is a C 1 –C 6 aliphatic group or a carbocyclic or heterocyclic group and R Z′ is H or a C 1 –C 6 aliphatic group;
R 3 is H or a C 1 –C 6 aliphatic group;
R 4 and R 5 are independently selected from H, halo, a C 1 –C 6 aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′ is an aliphatic, carbocyclic or heterocyclic group;
R 6 and R 7 are independently selected from H, halo or a C 1 –C 6 aliphatic group;
where any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and
where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
3. A compound of the Formula I-E:
wherein:
R 1 is a carbocyclic group;
R 2 is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;
W is N;
R 2′ is H or a C 1 –C 6 alkyl group or R 2 and R 2′ taken together with the atom W to which they are attached form an unsubstituted or substituted heterocyclic ring;
X is
wherein R x is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;
R 8 and R 8′ are each independently H, halo or a C 1 –C 4 aliphatic group;
Z is CH 2 , CHF, CF 2 , CH(OH), CH(O—R Z ), CH(N—R Z R Z′ ),
CH(S—R Z ), C(═O), or CH(R Z ), where R Z is a C 1 –C 6 aliphatic group or a carbocyclic or heterocyclic group and R Z′ is H or a C 1 –C 6 aliphatic group;
n is 1 or 2;
R 3 is H or a C 1 –C 6 aliphatic group;
R 4 is selected from H, halo, a C 1 –C 6 aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′ is an aliphatic, carbocyclic or heterocyclic group;
R 7 is H, halo or a C 1 –C 6 aliphatic group;
where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and
where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents, saturated, partially unsaturated or fully unsaturated or mono-, bi- or tri-cyclic;
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
4. A compound of the Formula I-F:
wherein:
R 1 is a carbocyclic group;
R 2 is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;
W is N;
R 2′ is H or a C 1 –C 6 alkyl group or R 2 and R 2′ taken together with the atom W to which they are attached form an unsubstituted or substituted heterocyclic ring;
X is
R x or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;
n is 1 or 2;
R 3 is H or a C 1 –C 6 aliphatic group;
R 4 and R 5 are independently selected from H, halo, a C 1 –C 6 aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′ is an aliphatic, carbocyclic or heterocyclic group;
R 6 and R 7 are independently selected from H, halo or a C 1 –C 6 aliphatic group;
R 8 and R 8′ are each independently H, halo or a C 1 –C 4 aliphatic group;
where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and
where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
5. A compound of the Formula I-G:
wherein:
R 1 is a carbocyclic group;
R 2 is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;
W is N;
R 2′ is H or a C 1 –C 6 alkyl group or R 2 and R 2′ taken together with the atom W to which they are attached form an unsubstituted or substituted heterocyclic ring;
X is
wherein R x is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;
R 8 and R 8′ are each independently H, halo or a C 1 –C 4 aliphatic group;
Z is CH 2 , CHF, CF 2 , CH(OH), CH(O—R Z ), CH(N—R Z R Z′ ),
CH(S—R Z ), C(═O), or CH(R Z ), where R Z is a C 1 –C 6 aliphatic group or a carbocyclic or heterocyclic group and R Z′ is H or a C 1 –C 6 aliphatic group;
n is 1, 2, 3 or 4;
R 3 is H or a C 1 –C 6 aliphatic group;
R 4 and R 5 are independently selected from H, halo, a C 1 –C 6 aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′ is an aliphatic, carbocyclic or heterocyclic group;
where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and
where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
6. A compound of the Formula I-E′:
wherein
R 1 is a carbocyclic;
R 2 is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;
W is N;
R 2′ is H or a C 1 –C 6 alkyl group;
X is
wherein R x is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;
Z is CH 2 , CHF, CF 2 , or CH(R Z ), where R Z is a C 1 –C 6 aliphatic group;
n is 1 or 2;
R 3 and R 4 are each H; and
R 7 is H;
wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and
wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;
or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.
7. The compound, prodrug, salt, or solvate according to claim 6 , wherein:
R 1 is a carbocyclic group;
R 2 is an arylalkyl group;
R 2′ is H;
X is
wherein R x is H; and
Z is CH 2 ;
wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, and hydroxy.
8. A compound of the Formula I-F′:
wherein:
R 1 is a carbocyclic group,
R 2 is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;
W is N;
R 2′ is H or a C 1 –C 6 alkyl group;
X is
wherein R x is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;
n is 1 or 2;
R 3 , R 4 and R 5 are each H; and
R 6 and R 7 and H;
wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and
wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;
or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.
9. The compound, prodrug, or salt, according to claim 8 , wherein:
R 1 is a carbocyclic group;
R 2 is an arylalkyl group;
R 2′ is H; and
X is
wherein R x is H;
wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy.
10. A compound of the Formula I-G′:
wherein:
R 1 is a carbocyclic group,
R 2 is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;
W is N;
R 2′ is H or C 1 –C 6 alkyl group;
X is
wherein R x is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;
Z is CH 2 , CHF, CF 2 , or CH(R Z ), where R Z is a C 1 –C 6 aliphatic group;
n is 2, 3 or 4;
R 3 , R 4 and R 5 are each H;
wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and
wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;
or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.
11. The compound, prodrug, salt, or salt according to claim 10 , wherein:
R 1 is a carbocyclic group;
R 2 is an arylalkyl group;
W is N;
R 2′ is H;
X is
wherein R x is H; and
Z is CH 2 ;
wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, and hydroxy.
12. The compound, prodrug, salt, or solvate according to claim 10 , wherein:
R 1 is a carbocyclic group;
R 2 is an arylalkyl group;
W is N;
R 2′ is H;
X is
wherein R x is H; and
Z is CF 2 ;
wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, and hydroxy.
13. A compound selected from:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
14. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
15. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
16. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
17. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
18. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
19. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
20. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
21. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
22. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
23. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.
24. A compound of the formula:
or a prodrug, pharmaceutically acceptable salt or solvate thereof.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.